DIAGNOSING EXERCISE-INDUCED BRONCHOCONSTRICTION WITH EUCAPNIC VOLUNTARY HYPERPNEA: IS ONE TEST ENOUGH?

Price et al DIAGNOSING EXERCISE-INDUCED BRONCHOCONSTRICTION WITH EUCAPNIC VOLUNTARY HYPERPNEA: IS ONE TEST ENOUGH? Oliver J Price1,3 MRes, Les Ansley1 PhD, James H Hull1, 2, PhD Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom (UK) Department of Respiratory Medicine, Royal Brompton Hospital, London, UK National Heart and Lung Institute, Imperial College London, London, UK Corresponding author: Dr James H Hull MRCP PhD Department of Respiratory Medicine, Royal Brompton Hospital, Fulham Road, London, SW3 6HP Tel: 0207 351 8091 Fax: 0207 351 8937 E-mail: j.hull@rbht.nhs.uk Word count: 3168 Abstract: 275 Running title: Reproducibility of eucapnic voluntary hyperpnea Price et al Funding statement: Nil relevant Highlights What is already known about this topic? Indirect bronchoprovocation testing, specifically eucapnic voluntary hyperpnoea (EVH) is currently recommended for the diagnosis of exercise-induced bronchoconstriction (EIB) However the clinical reproducibility of this methodology has yet to be appropriately established; presenting a potential for misdiagnosis What does this article add to our knowledge? This article highlights the need for caution when making a diagnosis of EIB based on a solitary EVH assessment to reduce the potential for misdiagnosis Indeed when encountering patients with a mild or borderline reduction in lung function post challenge, we recommend that more than one EVH test is performed to exclude or confirm a diagnosis of EIB How does this study impact current management guidelines? The application of treatment for EIB in recreational athletes should only be initiated when a diagnosis has been correctly established Price et al ABSTRACT Background: In athletic individuals, a secure diagnosis of exercise-induced bronchoconstriction (EIB) is dependent upon objective testing Indirect bronchoprovocation testing is often employed in this context and eucapnic voluntary hyperpnea (EVH) testing is recommended for this purpose, yet the short-term reproducibility of EVH has yet to be appropriately established Objective: The aim of this study was to evaluate the reproducibility of EVH in a cohort of recreational athletes Methods: A cohort of recreational athletes (n = 32) attended the laboratory on two occasions to complete an EVH challenge, separated by a period of 14 or 21 days Spirometry and impulse oscillometry (IOS) was performed before and following EVH Training load was maintained between visits Results: Pre-challenge lung function was similar at both visits (P>0.05) No significant difference was observed in maximum change in FEV (∆FEV1max) post EVH between visits (P>0.05) and test-retest ∆FEV1max was correlated (ICC = 0.81; r2 = 0.66; P = 0.001) Poor diagnostic reliability was observed between tests; eleven athletes were diagnosed with EIB (based on ∆FEV1max ≥10%) at visit and at visit However, only seven athletes were positive at both visits Whilst there was a small mean difference in ∆FEV 1max between tests (-0.6%) there were wide limits of agreement (-10.7 – 9.5%) Likewise, similar results were observed for IOS between visits Conclusion: In a cohort of recreational athletes, EVH demonstrated poor clinical reproducibility for the diagnosis of EIB These findings highlight a need for caution when confirming or refuting EIB based on a single indirect bronchoprovocation challenge When encountering patients with mild or borderline EIB, we recommend that more than one EVH test is performed to exclude or confirm a diagnosis Key words: Airway dysfunction, Athletes, Eucapnic voluntary hyperpnea, Exercise-induced bronchoconstriction, Indirect bronchoprovocation testing, Reproducibility Price et al Price et al ABBREVIATION LIST AQUA Allergy Questionnaire for Athletes AUC Area under the curve AX Area of reactance (area integrated from 5Hz to RF) BMI Body mass index CO2 Carbon dioxide EIB Exercise-induced bronchoconstriction EVH Eucapnic voluntary hyperpnea FEV1 Forced expiratory volume in one second FVC Forced vital capacity ICC Intra-class correlation IOC-MC International Olympic Committee-Medical commission IOS Impulse oscillometry LOA Limits of agreement MVV Maximal voluntary ventilation N2 Nitrogen O2 Oxygen R Resistance R5 Resistance at Hz R20 Resistance at 20 Hz RF Resonance frequency Price et al SABA Short acting beta-2 agonist SD Standard deviation X Reactance Z Impedance Z5 Magnitude of impedance at Hz Price et al INTRODUCTION Exercise-induced bronchoconstriction (EIB) describes the transient airway narrowing that occurs in association with exercise It is prevalent in both elite and recreational athletes (1) and may impact upon both their respiratory health and athletic performance (2-4) It is now well established that the diagnosis of EIB in athletes should not be based on clinical assessment alone (5-7) since a poor correlation exists between exercise-related symptoms and objective evidence of airway narrowing (8) As a consequence of this dissociation, current guidelines recommend that objective bronchoprovocation testing is employed to secure a diagnosis of EIB (9, 10) Exercise testing is frequently employed to diagnose EIB However, whilst an exercise test is ecologically valid and possesses good specificity for diagnosis, it has poor sensitivity and is limited by difficulties in controlling environmental conditions and exercise load and thus, the airway stimulus during a challenge (11) Indeed, poor short-term reproducibility of a laboratory exercise test for the diagnosis of EIB in a non-athletic group has previously been observed, with the conclusion that one test may not be enough to secure a diagnosis (12) Several ‘indirect’ airway challenges have been developed and recommended as surrogate means for diagnosing EIB The International Olympic Committee-Medical Commission (IOC-MC) (13) and several other guideline committees strongly endorse the eucapnic voluntary hyperpnea (EVH) challenge in this capacity (9, 10) The EVH challenge uses a compressed, dry gas as the stimulus for provoking bronchoconstriction with controlled hyperpnea The EVH test has been used and recommended for screening athletic cohorts for EIB (14, 15); with a positive ‘diagnosis’ being made from a single provocation test However, there is sparse data regarding the reproducibility of EVH (16, 17) and the inherent variability in any Price et al test has pragmatic implications for evaluating the effectiveness of a diagnostic tool in screening programmes and interventions Moreover, the reliability of EVH testing in the population of athletes in whom EVH screening has been advocated (i.e team squads (15, 18) at amateur or varsity level) has not been established In this population, the fall in FEV postchallenge can often be borderline (i.e 10-15% fall) and thus it is important to determine the stability and thus precision of such a result We therefore undertook this study with the aim of evaluating the test-retest reproducibility of EVH in a cohort of recreational athletes We proposed that there would be no difference in airway response following EVH between visits; i.e EVH would have good test-retest reproducibility A secondary aim was to evaluate the reproducibility of measures of small airway function utilising impulse oscillometry (IOS) over the same period of time Price et al MATERIALS AND METHODS Study population Thirty-six recreational athletes (training ± hours / week) (male: n = 31) from a variety of sporting disciplines; endurance (n = 22) (runners, cyclists and triathletes), intermittent highintensity (n = 11) (soccer, rugby and hockey), and non-endurance (n = 3) (weightlifters) were recruited to take part in the study All subjects were non-smokers, free from respiratory, cardiovascular, metabolic and psychiatric disease, and any other significant medical condition except mild asthma Six subjects had a physician-based diagnosis of mild asthma; all were prescribed a short acting beta-2 agonist (SABA) and two prescribed a regular inhaled corticosteroid Experimental design All subjects were required to attend the laboratory on two occasions separated by a period of either 14 or 21 days Subjects entered the laboratory 1-hr postprandial at a similar (± h) time of day for each visit An assessment of respiratory health and evaluation of allergy status was determined via completion of the Allergy Questionnaire for Athletes (AQUA) and aeroallergen skin prick testing Spirometry and impulse oscillometry (IOS) manoeuvres were performed pre and post an EVH provocation challenge (described below) Subjects were instructed to maintain their normal diet and physical activity levels throughout the duration of the study and compliance with this regime was assessed by interview Exclusion occurred if any alteration in training and/or health status/allergen exposure or respiratory tract infection was reported Subjects were asked to abstain from strenuous physical activity and SABA medication for 24 hrs and inhaled corticosteroid for 72 hrs, respectively, prior to each laboratory visit All tests and procedures were approved by the Price et al 10 local research ethics committee and all subjects provided written informed consent for experimentation with human subjects Atopic Status Sensitivity to seven common airborne allergens (early blossom tree, mid blossom tree, grass, weed, mould, cat and dust mite) were assessed via skin prick testing (19) Subjects also completed AQUA to assess allergic symptoms (20) An athlete was considered to be allergic if they presented with a positive skin prick test and a positive AQUA score ≥5 Pulmonary function Spirometry Lung function was assessed by forced flow-volume spirometry (MicroLoop ML3535; Cardinal Health, UK) (21) Subjects with airway obstruction at visit (FEV 1/FVC